Estrogen use in humans is associated with an increased risk of cancer. In rodents, estrogens induce mammary, pituitary, uterine, cervical, or kidney tumors. 2-Fluoroestradiol was previously shown in this laboratory to be estrogenic yet non-carcinogenic in the Syrian hamster renal carcinoma model. In this project, it is intended to establish the non-carcinogenic property of 2-fluoroestradiol in several other estrogen-induced tumor models and thus to generalize the concept of separation of estrogenicity from carcinogenicity by chemical modification. Specifically, lack of carcinogenic potential of 2-fluoroestradiol will be tested in 1. the estrogen and Alpha-naphthoflavone-induced liver tumor model in Syrian hamster, 2. in the estrogen-induced pituitary tumor model in Fischer 344 rats, and 3. in the estrogen/androgen-induced leiomyosarcoma of the uterine horns in Syrian hamster. In each of the three experiments, the tumor incidence will be compared with that of estradiol. Absorption from the estrogen implant and plasma estrogen levels will be measured. The estrogenic effect of the implant, pituitary LH and plasma prolactin, will be measured and compared with that of estradiol. Organ-specific DNA damage preceding carcinogenesis will be measured by a 32-P-postlabelling assay. The metabolism of 2-fluoroestradiol in rats and hamsters will be determined in vivo. In vitro, the conversion of 2-fluoroestradiol to catechol estrogens will be measured. These studies are designed to understand the mechanism of carcinogenesis by estrogens and the role of catechol estrogens in that process. Furthermore, the guiding principles for the design of a non-carcinogenic estrogen weill be developed.